Pathology of the FSGS Kidney

FSGS 肾脏的病理学

• 批准号: 7934590
• 负责人: AGNES B. FOGO
• 金额: $ 35.01万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7934590
• 关键词: Apoptotic; Arts; Attention; Biopsy; Cell Culture Techniques; Cell Cycle; Cell Death; Cell Differentiation process; Cells; Child; Cicatrix; Clinical; Disease; Dystroglycan; Elements; Epithelial Cells; Experimental Models; Extracellular Matrix; Fibrosis; Focal Segmental Glomerulosclerosis; Functional disorder; Future; Gelatinase A; Gelatinase B; Genomics; Health; Hilar; Histologic; Human; In Situ Nick-End Labeling; Infiltration; Inflammatory; Injury; Kidney; Lesion; Mediator of activation protein; Mesenchymal; Messenger RNA; Metalloproteases; Molecular; Multicenter Studies; Myofibroblast; NPHS2 protein; National Institute of Diabetes and Digestive and Kidney Diseases; Nature; Outcome; Pathology; Pathway interactions; Patients; Pattern; Phenotype; Plasminogen Activator Inhibitor 1; Play; Process; Prognostic Marker; Proteins; Proteomics; Randomized Controlled Trials; Role; Sclerosis; Specimen; Testing; Therapeutic; Tissues; Transforming Growth Factors; Tubular formation; case control; cell behavior; cell type; computerized; inflammatory modulation; inhibitor/antagonist; interstitial; interstitial cell; macrophage; mesangial cell; nephrin; new therapeutic target; podocyte; prognostic; promoter; prospective; response; response to injury; synaptopodin; translational study; young adult

DESCRIPTION (provided by applicant): While considerable progress has been achieved in understanding basic mechanisms of glomerular and renal fibrosis, the absence of a true experimental model for human FSGS has made it difficult to clearly understand how these basic mechanisms apply to human idiopathic FSGS. A second major limitation has been that mesenchymal cells such as mesangial cells and interstitial cells and tubular epithelial cells have received the most attention in defining pathways of sclerosis and fibrosis, while a less well studied cell, the podocyte, plays a major role in the injuries leading to FSGS. Recently, the NIDDK initiated a prospective, controlled, randomized trial to study the treatment of FSGS in children and young adults. Our studies aim to perform state-of-the art analysis of the renal biopsy tissue obtained for patient entry into this multicenter study, along with additional cases from our archival files, with a total of >2000 cases, with >200 in children. We will analyze histologic patterns of injury and correlate them with expression by specific glomerular cell types of protein and mRNA of mediators of cell differentiation, proliferation, ECM modulation and inflammatory modulators. These approaches will take advantage of the highly localized injuries in FSGS, i.e. the focal and segmental nature of the sclerosing lesions. Colocalization of mediators with expressions of candidate modulators of the disease process, as proposed in this project, is the first essential step in fulfilling Koch's postulates for establishing a causal role in disease, which can then be explored in complementary studies, e.g. cell culture, proteomic, genomic analyses in future studies. A key element will be the correlation of renal biopsy tissue findings with clinical outcome, to determine markers of prognosis and therapeutic response. These translational studies will utilize findings from the clinical specimens to provide an initial test of the putative pathogenetic roles of the leading molecular "suspects" that result in FSGS. These approaches could ultimately identify novel therapeutic targets in FSGS.

描述（由申请人提供）：虽然在理解肾小球和肾脏纤维化的基本机制方面已经取得了相当大的进展，但由于缺乏人类 FSGS 的真实实验模型，因此很难清楚地理解这些基本机制如何应用于人类特发性 FSGS。第二个主要限制是间充质细胞，如系膜细胞和间质细胞以及肾小管上皮细胞在定义硬化和纤维化途径方面受到最多关注，而研究较少的细胞，即足细胞，在损伤中发挥着主要作用导致 FSGS。最近，NIDDK 启动了一项前瞻性、对照、随机试验来研究儿童和年轻人 FSGS 的治疗。我们的研究旨在对参与这项多中心研究的患者获得的肾活检组织以及我们档案文件中的其他病例进行最先进的分析，总共超过 2000 例，其中超过 200 例为儿童。我们将分析损伤的组织学模式，并将其与特定肾小球细胞类型的细胞分化、增殖、ECM 调节和炎症调节介质的蛋白质和 mRNA 的表达相关联。这些方法将利用 FSGS 的高度局部损伤，即硬化性病变的局灶性和节段性。正如本项目所提出的，介质与疾病过程候选调节剂表达的共定位是实现科赫假设的第一个重要步骤，该假设建立了疾病中的因果作用，然后可以在补充研究中进行探索，例如：未来研究中的细胞培养、蛋白质组、基因组分析。一个关键因素是肾活检组织结果与临床结果的相关性，以确定预后和治疗反应的标志物。这些转化研究将利用临床标本的发现，对导致 FSGS 的主要分子“嫌疑人”的假定致病作用提供初步测试。这些方法最终可以确定 FSGS 的新治疗靶点。